This proposal will examine interactions involving the kidney, the renin-angiotensin-aldosterone system and the sympathetic nervous system by studying the role of the renal nerves in renovascular hypertension. Denervation of the clipped kidney in the one-kidney one-clip and the two-kidney one-clip rat with established hypertension results in a decrease in arterial pressure that is not explained by changes in renin or sodium excretion. This depressor effect of renal denervation is associated with decreased sympathetic nervous system activity. These findings led to the hypothesis that in response to clipping, the afferent renal nerves activate the sympathetic nervous system in the Goldblatt models of hypertension. To define the role of the renal nerves in the development of Goldblatt hypertension, the arterial pressure and sympathetic response to clipping will be compared in sham-operated and renal denervated animals chronically treated with converting enzyme inhibitor SQ 14225 (6 mg/kg/day) to prevent angiotensin II formation. Plasma norepinephrine and arterial pressure response to ganglionic blockade with 30 mg/kg hexamethonium bromide will be measured in conscious resting animals as indices of sympathetic nervous system activity. Recent studies by the investigator reveal that renal artery infusion of adenosine (0.85 plus or minus 0.08 Mug/kg/min) produces hypertension by activating the sympathetic nervous system when the renal nerves are intact in the conscious dog. This suggests that there may be adenosine sensitive nerve endings in the kidney which modulate sympathetic nervous system activity. To define the cardiac, contralateral renal efferent sympathetic and adrenal medullary responses to intrarenal adenosine, functional and neurophysiological studies will be performed before and after renal denervation in the chloralose anesthetized dog. Pilot studies reveal that intrarenal mineralocorticoid administration attenuates the hypertensive response to renal artery adenosine infusion in the conscious dog. To determine whether increased potassium and/or hydrogen ion excretion are involved in the mechanism by which mineralocorticoid treatmen blunts the intrarenal adenosine response, renal afferent nerve response to adenosine will be measured before and after increasing renal pelvic potassium and/or hydrogen ion concentrations in the anesthetized dog.